Regulation of Hepatic Inflammation via Macrophage Cell Death

Li, Zhuan; Weinman, Steven A.

doi:10.1055/s-0038-1670674

Cited by 32 publications

(25 citation statements)

References 159 publications

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“…Many studies have reported that the accumulation of hepatic macrophages plays a role in the pathogenesis of liver fibrosis by secreting pro‐inflammatory cytokines such as TNFα . Recent reports have also shown that dysregulated macrophage function contributes to the development of fibrosis and cell death and that apoptosis is a common response of hepatic macrophages to toxic insults . It was also shown that hepatic macrophages undergo apoptosis in fibrotic livers, possibly through the Fas‐mediated pathway .…”

Section: Discussionmentioning

confidence: 99%

“…18,19 Recent reports have also shown that dysregulated macrophage function contributes to the development of fibrosis and cell death and that apoptosis is a common response of hepatic macrophages to toxic insults. 20,21 It was also shown that hepatic macrophages undergo apoptosis in fibrotic livers, possibly through the Fas-mediated pathway. 22 Another study 23 reported that the apoptosis of M1 hepatic macrophages, which secrete pro-inflammatory mediators such as TNFα, plays a role in the pathogenesis of liver injury.…”

Section: Discussionmentioning

confidence: 99%

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Chitinase 3‐like 1 deficiency ameliorates liver fibrosis by promoting hepatic macrophage apoptosis

Higashiyama

Tomita

Sugihara

et al. 2019

Hepatology Research

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Aim Chitinase 3‐like 1 (CHI3L1), an 18‐glycosyl hydrolase‐related molecule, is a member of the enzymatically inactive chitinase‐like protein family. Serum levels of CHI3L1 are strongly correlated with hepatic fibrosis progression during many liver diseases. Therefore, this protein could be involved in the development of hepatic fibrosis pathology; however, its role has not been elucidated. We aimed to elucidate its role in the pathophysiology of liver fibrosis. Methods Chitinase 3‐like 1‐deficient (Chi3l1−/−) mice were given carbon tetrachloride twice per week for 4 weeks or fed a methionine choline‐deficient diet for 12 weeks to generate mouse liver fibrosis models. Human fibrotic liver tissues were also examined immunohistochemically. Results In human and mouse fibrotic livers, CHI3L1 expression was mainly localized to hepatic macrophages, and the intrahepatic accumulation of CHI3L1+ macrophages was significantly enhanced compared to that in control livers. In the two mouse models, hepatic fibrosis was significantly ameliorated in Chi3l1−/− mice compared to that in wild‐type mice, which was dependent on hepatic macrophages. The accumulation and activation of hepatic macrophages was also significantly suppressed in Chi3l1−/− mice compared to that in wild‐type mice. Furthermore, apoptotic hepatic macrophages were significantly increased in Chi3l1−/− mice. Chitinase 3‐like 1 was found to inhibit hepatic macrophage apoptosis by suppressing Fas expression and activating Akt signaling in an autocrine manner, which resulted in hepatic macrophage accumulation and activation, exaggerating liver fibrosis. Conclusions Chitinase 3‐like 1 exacerbates liver fibrosis progression by suppressing apoptosis in hepatic macrophages. Therefore, this might be a potential therapeutic target for the treatment of liver fibrosis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Chitinase 3‐like 1 deficiency ameliorates liver fibrosis by promoting hepatic macrophage apoptosis

Higashiyama

Tomita

Sugihara

et al. 2019

Hepatology Research

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“…Hepatic macrophages undergoing cell death, such as pyroptosis and necroptosis, are often observed during pathogen infection and sterile liver injury, and death of hepatic macrophages represents an important mechanism of bacterial clearance and inflammation resolution. 134 During infection by flagellin-expressing Salmonella typhimurium, Legionella pneumophila or Bukholderia thailandensis, caspase-1-induced pyroptosis of macrophages causes the release of ROS, which subsequently promotes the bacteria-killing activity of neutrophils. 135 Both Listeria monocytogenes and Salmonella enterica induce early rapid necroptosis of KCs in vivo.…”

Section: Roles Of Macrophages In Resolving Inflammation During Liver mentioning

confidence: 99%

Hepatic macrophages in liver homeostasis and diseases-diversity, plasticity and therapeutic opportunities

et al. 2020

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Macrophages, which are key cellular components of the liver, have emerged as essential players in the maintenance of hepatic homeostasis and in injury and repair processes in acute and chronic liver diseases. Upon liver injury, resident Kupffer cells (KCs) sense disturbances in homeostasis, interact with hepatic cell populations and release chemokines to recruit circulating leukocytes, including monocytes, which subsequently differentiate into monocyte-derived macrophages (MoMϕs) in the liver. Both KCs and MoMϕs contribute to both the progression and resolution of tissue inflammation and injury in various liver diseases. The diversity of hepatic macrophage subsets and their plasticity explain their different functional responses in distinct liver diseases. In this review, we highlight novel findings regarding the origins and functions of hepatic macrophages and discuss the potential of targeting macrophages as a therapeutic strategy for liver disease.

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“…For what concerns other severe complications of cirrhosis, e.g., portal hypertension-induced ascites, the role of other TAM system members has been demonstrated, with particular regard to MERTK. This prorestorative marker shows a two-faced activity: while for instance it is abundantly expressed in liver macrophages during the resolution phases of several diseases (e.g., acetaminophen-induced liver injury) [121], it has also been identified as a potent suppressor of T cell responses [122]. Regarding the latter activity, there are for instance some pieces of evidence about the development of immunoparesis in patients with acute on-chronic liver failure (ACLF) involving the unbalanced activation and overexpression of MERTK on monocytes/macrophages in the circulation and tissue sites of inflammation [123–125].…”

Section: Gas6/tam Receptorsmentioning

confidence: 99%

Gas6/TAM Signaling Components as Novel Biomarkers of Liver Fibrosis

et al. 2019

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Liver fibrosis consists in the accumulation of extracellular matrix components mainly derived from activated hepatic stellate cells. This is commonly the result of chronic liver injury repair and represents an important health concern. As liver biopsy is burdened with many drawbacks, not surprisingly there is great interest to find new reliable noninvasive methods. Among the many are new potential fibrosis biomarkers under study, some of the most promising represented by the growth arrest-specific gene 6 (Gas6) serum protein and its family of tyrosine kinase receptors, namely, Tyro3, Axl, and MERTK (TAM). Gas6/TAM system (mainly, Axl and MERTK) has in fact recently emerged as an important player in the progression of liver fibrosis. This review is aimed at giving an overall perspective of the roles played by these molecules in major chronic liver diseases. The most promising findings up to date acknowledge that both Gas6 and its receptor serum levels (such as sAxl and, probably, sMERTK) have been shown to potentially allow for easy and accurate measurement of hepatic fibrosis progression, also providing indicative parameters of hepatic dysfunction. Although most of the current scientific evidence is still preliminary and there are no in vivo validation studies on large patient series, it still looks very promising to imagine a possible future prognostic role for these biomarkers in the multidimensional assessment of a liver patient. One may also speculate on a potential role for this system targeting (e.g., with small molecule inhibitors against Axl) as a therapeutic strategy for liver fibrosis management, always bearing in mind that any such therapeutic approach might face toxicity.

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Regulation of Hepatic Inflammation via Macrophage Cell Death

Cited by 32 publications

References 159 publications

Chitinase 3‐like 1 deficiency ameliorates liver fibrosis by promoting hepatic macrophage apoptosis

Chitinase 3‐like 1 deficiency ameliorates liver fibrosis by promoting hepatic macrophage apoptosis

Hepatic macrophages in liver homeostasis and diseases-diversity, plasticity and therapeutic opportunities

Gas6/TAM Signaling Components as Novel Biomarkers of Liver Fibrosis

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